Synthesis of heteroarylamine intermediate compounds

ABSTRACT

Disclosed are novel 2-(5-halopyridyl) and 2-(5-halopyrimidinyl) magnesium halides, processes of making and their use in the efficient synthesis in their respective 5-halo-2-substituted pyridines and pyrimidines.

APPLICATION DATA

This application claims benefit to U.S. Provisional Application No.60/206,327 filed May 23, 2000.

FIELD OF INVENTION

The present invention relates to synthesis of heteroarylamineintermediate compounds.

BACKGROUND OF THE INVENTION

Aryl- and heteroaryl-substituted ureas have been described as inhibitorsof cytokine production. These inhibitors are described as effectivetherapeutics in cytokine-mediated diseases, including inflammatory andautoimmune diseases. Examples of such compounds are reported in WO99/23091 and in WO 98/52558.

A key step in the synthesis of these compounds is the formation of theurea bond. Various methods have been reported to accomplish this. Forexample, as reported in the above references, an aromatic orheteroaromatic amine, II, may be reacted with an aromatic orheteroaromatic isocyanate III to generate the urea IV (Scheme I)

If not commercially available, one may prepare the isocyanate III byreaction of an aryl or heteroaryl amine Ar₂NH₂ with phosgene or aphosgene equivalent, such as bis(trichloromethyl) carbonate(triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937)or trichloromethyl chloroformate (diphosgene) (K. Kurita, T. Matsumuraand Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanateIII, followed by reaction with Ar₁NH₂ to provide the urea. Otherapproaches to forming the urea reported in the chemical literatureinclude reaction of a carbamate with an aryl or heteroaryl amine, (seefor example B. Thavonekham, Synthesis, 1997, 1189 and T. Patonay et al.,Synthetic Communications, 1996, 26, 4253) as shown in Scheme II belowfor a phenyl carbamate. U.S. patent application Ser. No. 09/611,109 alsodiscloses a process of making heteroaryl ureas by reacting particularcarbamate intermediates with the desired arylamine.

U.S. application Ser. No. 09/505,582 and PCT/US00/03865 describecytokine inhibiting ureas of formula (I).

An Ar₂NH₂ required to prepare preferred compounds described therein isillustrated as formula (A).

wherein W, Y, and Z are described below.

The synthesis of II, a preferred formula (A) intermediate was describedin U.S. application Ser. No. 09/505,582 and PCT/US00/03865 and isillustrated in Scheme III.

The synthesis begins with a palladium catalyzed carbonylation of2,5-dibromopyridine (III) to provide ester IV in 55% yield. The reactionis run under pressure (80 psi CO) and must be monitored to minimizeformation of the diester, an unwanted by-product. Reduction of IV withdiisobutylaluminum hydride at −78° C. provides aldehyde V. This isfollowed by reductive amination to give VI.

Intermediate VI is then converted to II by reaction with t-BuLi at −78°C. followed by tributyltin chloride to give tributylstannane VII,followed by palladium catalyzed Stille coupling with intermediate VIIIto give II. Conversion of VI and analogous intermediates to otherintermediates of formula II via Suzuki coupling is also described inU.S. application Ser. No. 09/505,582 and PCT/US00/03865 (Scheme IV).According to this method, intermediate IX is treated with n-BuLifollowed by trimethylborate to give arylboronic acid X. Palladiumcatalyzed Suzuki coupling with VI provides XI, which is deprotected bytreatment with acid to give II.

This process is not well-suited for large-scale and commercial use forseveral reasons. One reaction (Scheme III) is run under high pressure(80 psi) and another at extreme temperature (−78° C.). The yield of IVis only moderate and by-product formation requires a purification step.These factors, plus the cost of starting materials and reagents makethis process too costly for commercial scale.

The preparation of 2-bromo-5-lithiopyridine via reaction of2,5-dibromopyridine with n-BuLi at −100° C. has been described (W. E.Parham and R. M. Piccirilli, J. Org. Chem., 1977, 42, 257). Theselective formation of 2-bromo-5-pyridinemagnesium chloride via reactionwith 2,5-dibromopyridine with i-PrMgCl at 0° C.—rt has also beenreported (F. Trecourt et al., Tetrahedron Lett., 1999, 40, 4339). Inthese cases, the metal-halogen exchange occurred exclusively at the 5position of the pyridine ring. However, the syntheses of 5-bromobromo-2-pyridinemagnesium chloride and 5-chloro-2-pyridinemagnesiumchloride have not been reported previously.

The preparation of a lithium intermediate 5-chloro-2-lithiopyridine from2-bromo-5-chloropyridine, has been reported (U. Lehmann et al., Chem.,Euro. J., 1999, 5, 854). However, this synthesis requires reaction withn-BuLi at −78° C. The preparation of the 5-bromo-2-lithiopyridine from2,5-dibromopyridine was reported by X. Wang et al. (Tetrahedron Letters,2000, 4335). However, the method requires cryogenic and high dilutionconditions. The selectivity was also dependent on reaction time. It isnot suitable for large scale synthesis.

The synthesis of the intermediate 5-bromo-2-iodopyridine by refluxing2,5-dibromopyridine in HI has been reported (U. Lehmann, ibid). Aprocess using milder conditions for preparing 2-iodopyridine from2-chloro or 2-bromopyridine has been described (R. C. Corcoran and S. H.Bang, Tetrahedon Lett., 1990, 31, 6757).

SUMMARY OF THE INVENTION

It is an object of the invention to provide novel 2-(5-halopyridyl) and2-(5-halopyrimidinyl) magnesium halides, novel methods of producingthem, and to provide a novel method of using said halides in theefficient synthesis of their respective 5-halo-2-substituted pyridinesand pyrimidines.

It also an object of the invention to provide a novel method ofproducing heteroaryl amines of the formula(A)

wherein Ar, W, Y and Z are described below, the heteroaryl amines areuseful in the production of heteroaryl ureas as mentioned above.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a novel strategy for the synthesis ofheteroarylamine compounds of the formula (A) which constitute the keycomponent of pharmaceutically active compounds possessing a heteroarylurea group.

The invention therefore provides for processes of making a compound ofthe formula(A)

wherein:

W is CR₃ or N, wherein R₃ is chosen from hydrogen, C₁₋₅alkyl,C₁₋₅alkoxy, arylC₀₋₅alkyl and —COR₄ wherein R₄ is chosen from C₁₋₅alkyl,C₁₋₅alkoxy, arylC₀₋₅alkyl and amino which is optionally independentlydi-substituted by C₁₋₅alkyl, and arylC₀₋₅alkyl; W is preferably CH or N,

Ar is chosen from

phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl,dihydrobenzothienyl, indanyl, indenyl and indolyl each being optionallysubstituted by one or more R₁ or R₂;

Y is chosen from

a bond and a C₁₋₄ saturated or unsaturated branched or unbranched carbonchain optionally partially or fully halogenated, wherein one or moremethylene groups are optionally replaced by O, N, or S(O)_(m) andwherein Y is optionally independently substituted with one to two oxogroups, phenyl or one or more C₁₋₄ alkyl optionally substituted by oneor more halogen atoms;

wherein when Y is the carbon chain, the left side terminal atom of Y isa carbon (the atom which is covalently attached to the heterocyclepossessing W):

Z is chosen from:

aryl, heteroaryl chosen from pyridinyl, piperazinyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, furanyl,thienyl and pyranyl and heterocycle chosen from tetrahydropyrimidonyl,cyclohexanonyl, cyclohexanolyl, 2-oxo- or2-thio-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl,pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylenesulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl,tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl,1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl,thiomorpholinyl sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl anddioxolanyl, each of the aforementioned Z are optionally substituted withone to three halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl,C₁₋₆ alkoxycarbonyl, aroyl, C₁₋₃acyl, oxo, pyridinyl-C₁₋₃ alkyl,imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃ alkyl,nitrile, phenyl wherein the phenyl ring is optionally substituted withone to two halogen, C₁₋₆ alkoxy or mono- or di-(C₁₋₃ alkyl)amino, C₁₋₆alkyl-S(O)_(m), or phenyl-S(O)_(m) wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy, halogen or mono- ordi-(C₁₋₃ alkyl)amino;

or Z is optionally substituted with one to three amino or amino-C₁₋₃alkyl wherein the N atom is optionally independently mono- ordi-substituted by aminoC₁₋₆alkyl, C₁₋₃alkyl, arylC₀₋₃alkyl, C₁₋₅alkoxyC₁₋₃ alkyl, C₁₋₅ alkoxy, aroyl, C₁₋₃acyl, C₁₋₃alkyl-S(O)_(m)— orarylC₀₋₃alkyl-S(O)_(m)— each of the aforementioned alkyl and arylattached to the amino group is optionally substituted with one to twohalogen, C₁₋₆ alkyl or C₁₋₆ alkoxy;

or Z is optionally substituted with one to three aryl, heterocycle orheteroaryl as hereinabove described in this paragraph each in turn isoptionally substituted by halogen, C₁₋₆ alkyl or C₀₋₆ alkoxy;

or Z is nitrile, amino wherein the N atom is optionally independentlymono- or di-substituted by C₁₋₆alkyl or C₁₋₃alkoxyC₁₋₃alkyl, C₁₋₆alkylbranched or unbranched, C₁₋₆alkoxy, nitrileC₁₋₄alkyl, C₁₋₆alkyl-S(O)_(m), aryl chosen from phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,furanyl, thienyl and pyranyl each aryl being optionally substituted withone to three halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, di-(C₁₋₃ alkyl)amino,C₁₋₆ alkyl-S(O)_(m), or nitrile, and phenyl-S(O)_(m), wherein the phenylring is optionally substituted with one to two halogen, C₁₋₆ alkoxy ormono- or di-(C₁₋₃ alkyl)amino;

R₁ and R₂ are independently chosen from: a C₁₋₆ branched or unbranchedalkyl optionally partially or fully halogenated, acetyl, aroyl, C₁₋₄branched or unbranched alkoxy, each being optionally partially or fullyhalogenated, halogen, methoxycarbonyl, C₁₋₃ alkyl-S(O)_(m) optionallypartially or fully halogenated, or phenylsulfonyl;

m=0, 1 or 2;

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₆alkoxy” is a C₁₋₆alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkenyl andalkynyl groups shall be understood as being branched or unbranched wherestructurally possible and unless otherwise specified. Other morespecific definitions are as follows:

Ac—acetyl;

DBA—dibenzylideneacetone;

DPPF—1,1′-bis(diphenylphosphino)ferrocene;

DPPE—1,2-bis(diphenylphosphino)ethane;

DPPB—1,4-bis(diphenylphosphino)butane;

DPPP—1,3-bis(diphenylphosphino)propane;

BINAP—2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;

DME—ethylene glycol dimethylether;

DMSO—dimethyl sulfoxide;

DMF—N,N-dimethylformamide;

EtO—ethoxide;

^(i)Pr—isopropyl;

^(t)Bu—tertbutyl;

THF—tetrahydrofuran;

RT or rt—room temperature;

The term “aroyl” as used in the present specification shall beunderstood to mean “benzoyl” or “naphthoyl”.

The term “aryl” as used herein shall be understood to mean aromaticcarbocycle, preferably phenyl and naphthyl, or heteroaryl.

The term “heterocycle”, unless otherwise noted, refers to a stablenonaromatic 4-8 membered (but preferably, 5 or 6 membered) monocyclic ornonaromatic 8-11 membered bicyclic heterocycle radical which may beeither saturated or unsaturated. Each heterocycle consists of carbonatoms and one or more, preferably from 1 to 4 heteroatoms selected fromnitrogen, oxygen and sulfur. The heterocycle may be attached by any atomof the cycle, which results in the creation of a stable structure.Unless otherwise stated, heterocycles include but are not limited to,for example oxetanyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylenesulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl,homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl,decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl,dihydropyranyl, oxocanyl, heptacanyl, thioxanyl, dithianyl or 2-oxa- or2-thia-5-aza-bicyclo[2.2.1]heptanyl.

The term “heteroaryl”, unless otherwise noted, shall be understood tomean an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ringcontaining 1-4 heteroatoms such as N, O and S. Unless otherwise stated,such heteroaryls include: pyridinyl, pyridonyl, quinolinyl,dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl,tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl,benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl,benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl,indolinyl, indolonyl, indolinonyl, phthalimidyl.

Terms which are analogs of the above cyclic moieties such as aryloxy orheteroaryl amine shall be understood to mean an aryl, heteroaryl,heterocycle as defined above attached to it's respective functionalgroup.

As used herein, “nitrogen” and “sulfur” include any oxidized form ofnitrogen and sulfur and the quaternized form of any basic nitrogen.

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine except asotherwise noted. The compounds made by the novel processes of theinvention are only those which are contemplated to be ‘chemicallystable’ as will be appreciated by those skilled in the art. For example,a compound which would have a ‘dangling valency’, or a ‘carbanion’ arenot compounds made by processes contemplated by the invention.

In one embodiment of the invention there is provided a process of makingthe compounds of formula(A) as described hereinabove,

said process comprising:

a) synthesis of a compound of formula (C) from a compound of formula (B)via substitution with an appropriate halide X_(c). When X_(c) is Br,methods known in the art may be utilized.

When X_(c) is I, the present invention provides a novel process for thesubstitution of the leaving group (L) with iodide. This was achieved byusing the conditions of R_(x)COCl or (R_(x)CO)₂O/metaliodide/solvent/heating (25° C.-150° C.), wherein R_(x) is chosen from—C₁₋₇ alkyl, —CF₁₋₃ and —CCl₁₋₃; the metal chosen from Na and K, and thesolvent chosen from acetonitrile, acetone, DMSO, DMF and THF. Preferredconditions are AcCl and NaI in acetonitrile at 70-90° C. The leavinggroup L is any suitable leaving group as will be appreciated by thoseskilled in the art, preferably L is chosen from Cl, Br, —OCOR_(y) and—OS(O)_(m)R_(y), wherein R_(y) is aryl optionally substituted byC₁₋₄alkyl optionally halogenated, such as tolyl, or R_(y) is C₁₋₄alkyloptionally halogenated such as CF₃ and CCl₃, L is more preferably chosenfrom Br and Cl.

 X_(a) is chosen from Br and Cl, preferably Br;

X_(c) is I or Br, preferably I;

X_(a) is attached via the 4 or 5 ring position, preferably the 5position.

b) In a one pot process, reacting a compound of the formula(C) with aGrignard reagent R—Mg—X_(b) followed by the addition of an E—Y—Zcompound wherein Y—Z is as defined above, said E—Y—Z component isfurther characterized as being an electrophilic derivative of Y—Z andbeing appropriate for Grignard reagant reactions as will be apparent tothe skilled artisan, said reaction taking place in a suitable aproticsolvent at −78° C. to RT, preferably 0° C. to RT for a reaction time of½ hour to 2 hours, preferably 1 hour, and isolating the compound of theformula (D);

 wherein:

X_(b) is chosen from Br, Cl and I;

R is aryl, C₁₋₆alkyl or C₅₋₇cycloalkyl;

As seen in Scheme V below, this one pot novel process step provides forthe formation of the Grignard reagant Compound (F):

where a desirable selective formation was observed. For example thesynthesis of 2-(5-halopyridyl)magnesium halides (e.g. 3 and 12) wasachieved for the first time.

The process of making compounds of the formula(F) comprises:

reacting a compound of the formula(C)

 with a magnesium reagent of the formula R—MgX_(b); said reaction takingplace in a suitable aprotic solvent at −78° C. to RT, for a reactiontime of ½ hour to 2 hours, producing the Grignard compound of theformula(F);

and wherein

X_(a), is halogen selected from Br and Cl, and X_(a) is attached via the4 or 5 ring position;

X_(b) is halogen chosen from Br, Cl and I;

X_(c) is I or Br;

W is CR₃ or N, wherein R₃ is chosen from hydrogen, C₁₋₅alkyl,C₁₋₅alkoxy, arylC₀₋₅alkyl and —COR₄ wherein R₄ is chosen from C₁₋₅alkyl,C₁₋₅alkoxy, arylC₀₋₅alkyl and amino which is optionally independentlydi-substituted by C₁₋₅alkyl or arylC₀₋₅alkyl; W is preferably CH or N;

preferably CH or N; and

R is aryl, C₁₋₆alkyl or C₅₋₇cycloalkyl.

In a preferred embodiment there is provided a process for making acompound of the formula(F) as described above and wherein

W is CH;

X_(a) is Br and attached at the 5 ring position;

X_(c) is I;

the temperature is 0° C. to RT; and

the reaction time is 1 hour.

Non-limiting examples of this reaction proceeded with completeselectivity at the 2 position in excellent yield:

In subsequent steps, the novel process of the invention furthercomprises:

c) reacting the compound of the formula(D) from step b) with an arylboronic acid of the formula (E), in the presence of a catalyst chosenfrom nickel and palladium. Regarding the palladium(Pd) catalyst,non-limiting examples are Pd catalysts chosen from Pd(PPh₃)₂Cl₂,Pd(PPh₃)₄, PdCl₂(DPPE), PdCl₂(DPPB), PdCl₂(DPPP), PdCl₂(DPPF) and Pd/C;or the combination of a palladium source and an appropriate ligand, withthe Pd source, for example, being chosen from PdCl₂, Pd(OAc)₂,Pd₂(DBA)₃, Pd(DBA)₂, and with the ligand being chosen from PPh₃, DPPF,DPPP, DPPE, DPPB, P(o-tolyl)₃, P(2,4,6-trimethoxyphenyl)₃, AsPh₃,P(^(t)Bu)₃, BINAP, and those bound to solid supports that are mimics ofthe aforementioned ligands, preferably PdCl₂ and PPh₃. Regarding thenickel(Ni) catalyst, examples of nickel (Ni) catalyst are those chosenfrom Ni(PPh₃)₂Cl₂, Ni(PPh₃)₄, NiCl₂(DPPE), NiCl₂(DPPB), NiCl₂(DPPP),NiCl₂(DPPF) and Ni/C; or the combination of a Ni source and anappropriate ligand, with the Ni source being NiCl₂, and with the ligandbeing chosen from PPh₃, DPPF, DPPP, DPPE, DPPB, P(o-tolyl)₃,P(2,4,6-trimethoxyphenyl)₃, AsPh₃, P(^(t)Bu)₃, BINAP, and those bound tosolid supports that are mimics of the aforementioned ligands. Thisreaction takes place in a suitable solvent such as ethylene glycoldimethyl ether (DME), THF, toluene, methylene chloride or water,preferably DME, at 0° C. to 150° C., preferably 25° C. to 100° C., for aperiod of 1 to 24 hours preferably about 15 hours,

wherein P in the formula(E) is an amino protecting group such as Boc,and subsequently removing said protecting group under suitableconditions to produce a compound of the formula(A).

In a preferred embodiment of the invention there is provided a novelprocess of making compounds of the formula(A) as described above andwherein:

W is CH;

Ar is chosen from naphthyl, quinolinyl, isoquinolinyl,tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,indanyl, indenyl and indolyl each being optionally substituted by one ormore R₁ or R₂ groups;

Y is chosen from:

a bond and

a C₁₋₄ saturated or unsaturated carbon chain wherein one of the carbonatoms is optionally replaced by O, N, or S(O)_(m) and wherein Y isoptionally independently substituted with one to two oxo groups, phenylor one or more C₁₋₄ alkyl optionally substituted by one or more halogenatoms; wherein when Y is the carbon chain, the left side terminal atomof Y is a carbon (the atom which is covalently attached to theheterocycle possessing W):

Z is chosen from:

phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl,furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl,pyranyl, pyrrolidinyl which are optionally substituted with one to threenitrile, C₁₋₃ alkyl, C₁₋₃ alkoxy, amino or mono- or di-(C₁₋₃alkyl)amino;

tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl,1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl,piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl,pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylenesulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl ortetramethylene sulfonyl which are optionally substituted with one tothree nitrile, C₁₋₃ alkyl, C₁₋₃ alkoxy, amino or mono- or di-(C₁₋₃alkyl)amino;

nitrile, C₁₋₆ alkyl-S(O)_(m), halogen, C₁₋₄ alkoxy, amino, mono- ordi-(C₁₋₆ alkyl)amino and di-(C₁₋₃ alkyl)aminocarbonyl;

In a more preferred embodiment of the invention there is provided anovel process of making compounds of the formula(A) as describedimmediately above and wherein:

Ar is naphthyl;

Y is chosen from:

a bond and

a C₁₋₄ saturated carbon chain wherein the left side terminal atom of Yis a carbon (the atom which is covalently attached to the heterocyclepossessing W) and one of the other carbon atoms is optionally replacedby O, N or S and wherein Y is optionally independently substituted withan oxo group;

Z is chosen from:

phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl,dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl and pyrrolidinylwhich are optionally substituted with one to two C₁₋₂ alkyl or C₁₋₂alkoxy;

tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinylsulfoxidyl, piperidinyl, piperidinonyl, piperazinyl andtetrahydropyrimidonyl which are optionally substituted with one to twoC₁₋₂ alkyl or C₁₋₂ alkoxy; and C₁₋₃ alkoxy;

In yet a more preferred embodiment of the invention there is provided anovel process of making compounds of the formula(A) as describedimmediately above and wherein:

Ar is 1-naphthyl wherein the NH₂ is at the 4 position;

Y is chosen from:

a bond, —CH₂—, —CH₂CH₂— and —C(O)—;

In an ultimately preferred embodiment of the invention there is provideda novel process of making compounds of the formula(A) as describedimmediately above and wherein:

Y is

—CH₂—;

Z is morpholinyl;

Formation of the reaction intermediate (E) can be accomplished by firstprotecting an aryl-amine followed by boronic acid formation through asequence of metal-bromine exchange, quenching with trialkylborate andhydrolysis, as can be seen in Scheme V in the conversion of 7 to 9.Compounds of the formula (E) possessing other desired Ar can beaccomplished without undue experimentation by variations apparent tothose of ordinary skill in the art in view of the teachings in thisspecification and the state of the art.

A desirable novel feature of the process of the invention is theselective formation of a 2-(5-halopyridyl) or 2-(5-halopyrimidinyl)magnesium halides, preferably 2-(5-halopyridyl) magnesium halides (e.g.3 and 12, vide infra), and their subsequent reactions with the in situgenerated E—Y—Z electrophiles. Below in Scheme 1, the addition of2-(5-halopyridyl) magnesium halide 3 to the immonium salt 6 was carriedout without the isolation of the immonium salt.

A non-limiting example for a compound of the formula (A) is the amine 1shown in Scheme V.

Reaction intermediate (2) with a generic formula (B) above can beobtained as exemplified in Scheme VI below. Addition of a coppercatalyst may be required for transformations involving certain types ofelectrophiles, for example the alkylation reaction of the Grignardintermediate with various alkyl halides and epoxides.

Examples of appropriate electrophiles are shown in the table below.Methods of making Y—Z electrophilic derivatives are within the skill inthe art. Y component in Y—Z is a derivative of the Y of the formula (A)of the final product upon the addition of the electrophile to theGrignard intermediate. Products may be further derivatized to achievethe desired Y—Z. Such further transformations are within the skills inthe art. A non-limiting example is shown below for a preferredembodiment of Z in the formula (A), i.e., the morpholino immonium salt6. Reference in this regard may be made to Heaney, H.; Papageorgiou, G.;Wilkins, R. F. Tetrahedron 1997, 53, 2941; Sliwa, H.; Blondeau, D.Heterocycles 1981, 16, 2159;.

In this example, E—Y—Z is compound 6, wherein morpholinyl represents Zand Y is —CH₂— in the final product.

As described above, any electrophile represented by Y, possessing a Zcomponent and compatible with Grignard type reactions are contemplatedto be within the scope of the invention. Additional non-limitingexamples of E—Y—Z are:

wherein E—Y is an aldehyde such as Z—CHO, thus Y in Formula (A) would be—CH(OH)—.

wherein NRR represent any of the above-listed Z amine moieties orheterocycles possessing a nitrogen heteroatom and Y can be alkylene suchas —CH₂—, X is a countervalent anion.

wherein E—Y is a branched or unbranched alkoxy possessing a halogen atomX and further linked to Z, such as ClCH₂—O—Z.

wherein E—Y is a C₁₋₄acyl halide such as formylchloride, NRR′ representsany of the above-listed Z amine moieties, or heterocycles possessing anitrogen heteroatom. LG is an appropriate leaving group such ashalogens. (see: Katritzky et al., J. Chem. Res. 1999, 3, 230.)

wherein E—Y is a haloester moiety such as chloroformate. X is anappropriate leaving group such as halogens or alkoxy groups. (see:Satyanarayana et al., Synth. Commun. 1990, 20 (21), 3273.)

Z—Y—X   6.

wherein an appropriate Z—Y is substituted by halogen X, preferablyiodine, such as CH₃I.

Addition of an appropriate Z attached to a reactive epoxide provides thehydroxy intermediate which is further derivatized to the desired Ycomponent.

Acylation wherein Y is an acyl attached to Z may be accomplished via theappropriate acylation reagent such as the ester shown above wherein —ORis a known leaving group.

In another embodiment of the invention there is provided a process ofmaking the compounds of formula(A):

wherein Ar and W are as described above;

and wherein for the formula(A):

Y is —CH₂—; and

Z is chosen from: heterocycle chosen from morpholinyl, thiomorpholinyl,piperidinyl and pyrrolidinyl each of the aforementioned Z are optionallysubstituted with one to three halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃alkoxy-C₁₋₃ alkyl, C₁₋₆ alkoxycarbonyl, aroyl, C₁₋₃acyl, oxo,pyridinyl-C₁₋₃ alkyl, imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃alkyl, nitrile-C₁₋₃ alkyl, nitrile, phenyl wherein the phenyl ring isoptionally substituted with one to two halogen, C₁₋₆ alkoxy, di-(C₁₋₃alkyl)amino, C₁₋₆ alkyl-S(O)_(m), or phenyl-S(O)_(m) wherein the phenylring is optionally substituted with one to two halogen, C₁₋₆ alkoxy ordi-(C₁₋₃ alkyl)amino;

or Z is optionally substituted with one to three one to three amino oramino-C₁₋₃ alkyl wherein the N atom is optionally independentlydi-substituted by aminoC₁₋₆alkyl, C₁₋₃alkyl, arylC₀₋₃alkyl, C₁₋₅alkoxyC₁₋₃ alkyl, C₁₋₅ alkoxy, aroyl, C₁₋₃acyl, C₁₋₃alkyl-S(O)_(m)— orarylC₀₋₃alkyl-S(O)_(m)— each of the aforementioned alkyl and arylattached to the amino group is optionally substituted with one to twohalogen, C₁₋₆ alkyl or C₁₋₆ alkoxy; or Z is optionally substituted withone to three aryl or heterocycle as hereinabove described in thisparagraph each in turn is optionally substituted by halogen, C₁₋₆ alkylor C₁₋₆ alkoxy;

or Z is amino wherein the N atom is optionally independently mono- ordi-substituted by C₁₋₆alkyl or C₁₋₃alkoxyC₁₋₃alkyl, C₁₋₆alkyl branchedor unbranched, C₁₋₆alkoxy, nitrileC₁₋₄alkyl, C₁₋₆ alkyl-S(O)_(m), arylchosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl andpyranyl each aryl being optionally substituted with one to threehalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, di-(C₁₋₃alkyl)amino, C₁₋₆alkyl-S(O)_(m) or nitrile, and phenyl-S(O)_(m), wherein the phenyl ringis optionally substituted with one to two halogen, C₁₋₆ alkoxy or mono-or di-(C₁₋₃ alkyl)amino;

said reaction comprising:

reacting a compound of the formula(C)

 with a magnesium reagent of the formula R—MgX_(b); said reaction takingplace in a suitable aprotic solvent at −78° C. to RT, for a reactiontime of ½ hour to 2 hours producing the Grignard compound(F):

 wherein

X_(a), is halogen selected from Br and Cl, and X_(a) is attached to thering via the 4 or 5 position;

X_(b) is halogen chosen from Br, Cl and I;

X_(c) is I or Br;

W is CH, CCH₃ or N; and

R is aryl, C₁₋₆alkyl or C₅₋₇cycloalkyl;

subsequently reacting the Grignard compound from the prior step with aN,N-dialkylformamide such as DMF to form an aldehyde:

and isolating the aldehyde;

reacting the aldehyde with an appropriate Z group under nucleophilicaddition conditions to provide the compound (D)

This transformation is within the skill in the art and involves reactingof the aldehyde and the appropriate Z component under acidic conditionssuch as HCl, AcOH, H₂SO₄ etc, preferably AcOH, in a suitable solventsuch as THF, methylene chloride, 1,2-dichloroethane, preferably1,2-dichloroethane for 0.5-5 h (preferably 2 h) at about RT followed byin situ reduction for 0.5-5 h (preferably 2 h) to provide the product(D).

Subsequent addition of the NH₂—Ar compound can be done as describedhereinabove, to provide the final product compound of the formula(A) asdescribed above in this embodiment of the invention. A non-limitingexample of this embodiment of the invention is shown in Scheme VII.

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustrating preferred embodiments of this invention, and are not to beconstrued as limiting the scope of the invention in any way.

SYNTHETIC EXAMPLES Example 1

Synthesis of 5-bromo-2-iodopyridine from 2,5-dibromopyridine

2,5-Dibromopyridine (100 g) was suspended in acetonitrile (500 mL) atrt. NaI (94 g) and AcCl (45 mL) were added and the reaction was thengently refluxed for 3 h. An aliquot was analyzed by ¹H NMR and MS andthe reaction was about 80% complete. The reaction was cooled to rt andquenched with a few mL of water and then K₂CO₃ aqueous solution to pH 8.EtOAc (1.5 L) was added to extract the organic materials. The organiclayer was washed with saturated NaHSO₃ solution, the brine, and thendried over MgSO₄. Concentration gave crude material that was subjectedto the same conditions for about 3 h at which time ¹H NMR showed thatthe reaction was greater than 97% complete. The same workup provided thecrude material. The crude crystals were washed twice with CB₃CN anddried in the oven. The yield was 95 g.

¹H NMR (CDCl₃, 400 MHz) δ8.44 (s, 1H), 7.60 (d, J=8.26 Hz, 1H), 7.44 (d,J=8.25 Hz, 1H).

Example 2

Synthesis of 5-bromo-2-formylpyridine from 5-bromo-2-iodopyridine viathe Grignard intermediate

In a 22 L 3-neck round bottomed flask equipped with a mechanicalstirrer, 1 kg (3.52 mol) of 2-iodo-5-bromopyridine was dissolved in 5 Lof THF. The solution was cooled to about −15 to −10° C. 1.9 L (2 M, 380mol, 1.08 eq) of ^(i)PrMgCl was added at a rate to keep the internaltemperature below 0° C. The reaction mixture became a brown suspension.After the reaction mixture was stirred between −15 to 0° C. for 1 h, 400mL (5.16 mol, 1.5 eq) of DMF was added at a rate to keep the internaltemperature below 0° C. After stirring at this temperature for 30 min,the cooling bath was removed and the reaction was allowed to warm toroom temperature over 1 h. The reaction mixture was then cooled to 0° C.and 4.0 L (7.74 mol, 2.2 eq) of 2 N HCl was added at a rate to keep theinternal temperature below 25° C. The mixture was stirred for 30 min,then pH was raised from 1 to a pH 6-7 by adding about 150 mL of 2 NNaOH. The layers were separated and the THF layer was concentrated togive dark brown wet solids. The aqueous layer was extracted with 3 L ofCH₂Cl₂. The CH₂Cl₂ layer was used to dissolve the residue obtained fromthe THF layer, the resulting solution was washed with water (2×2 L),dried by stirring with MgSO₄ (400 g) for 30 min, and filtered.Concentration of the filtrate to dryness gave 583 g of the desiredaldehyde as brownish-yellow solids (89% yield after air drying).

¹H NMR (CDCl₃, 400 MHz) δ10.04 (d, J=0.68 Hz, 1H), 8.86 (t, J=0.52 Hz,1H), 8.02 (dt, J=8.20, 0.68 Hz, 1H), 7.85 (d, J=8.48 Hz, 1H).

Example 3

Synthesis of 5-bromo-2-(4-morpholinylmethyl)pyridine from5-bromo-2-iodopyridine via the Grignard intermediate

To a solution of bis(1-morpholinyl)methane (130 mg) in THF (3 mL) at rtwas added acetyl chloride (45 mL). The reaction was stirred for 1 h andcooled to 0° C.

In another flask, 5-bromo-2-iodopyridine (130 mg) was dissolved in THF(3 mL) at −40° C. The solution was treated with ^(i)PrMgCl (2 M in THF,0.39 mL) at the same temperature for 15 min. Then the Grignard solutionwas cannulated into the immonium salt suspension generated above at 0°C. After the addition, the reaction mixture was stirred at rt for 1 hand quenched with saturated NH₄Cl solution. Extraction with CH₂Cl₂,drying over MgSO₄, filtration and concentration gave a crude oil. Thiswas further purified by column chromatography to afford the product inabout 50% yield.

¹H NMR (CDCl₃, 400 MHz) δ8.60 (s, 1H), 7.76 (d, J=8.24 Hz, 1H), 7.32 (d,J=8.64 Hz, 1H), 3.72 (m, 4H), 3.59 (s, 2H), 2.48 (m, 4H).

Example 4

Synthesis of 5-bromo-2-(4-morpholinyl)methylpyridine from5-bromo-2-formylpyridine

To a solution of 500 g (2.688 moles) aldehyde in a 5 L of 1,2-dichloroethane at room temperature was added morpholine (1.15 eq, 3.09moles, 269 ml) in one portion. The reaction temperature went up to 29°C. After stirring the reaction mixture for 15 min, acetic acid (2.1 eq,5.6 moles, 323 mL) was added in one portion. The temperature rose to 31°C. It was stirred for 1.5 h at room temperature. Sodiumtriacetoxyborohydride (1.06 eq, 2.85 moles, 604 g ) was added in 100 gportions every 10 min. The temperature was maintained between 35° C. and46° C. by gentle cooling. It was stirred for an additional 2 h.

The reaction mixture was quenched with 4 N HCl keeping the temperaturebelow 15° C. At the end of addition, the pH of aqueous phase was between0 and 1 (˜2200 mL). The organic phase was separated and discarded. Theaqueous phase was basified with 9 N NaOH (˜740 g NaOH) to pH˜9.5 keepingthe internal temperature below 15° C. The product was extracted withmethylene chloride. Evaporation of the solvent gave pure amine (660 g,2.57 moles).

Example 5 Synthesis of 5-Bromo-3-methyl-2-pyridinecarboxaldehyde

An example of the synthesis of a compound of formula (F) in which W isCR₃ (R₃=methyl), and subsequent reaction with an electrophile isprovided below and illustrated in Scheme VIII.

2,5-Dibromo-3-picoline is commercially available or may be prepared from2-amino-5-bromo-3-methylpyridine by standard diazotization followed bybromination in Br₂/HBr. Acetyl chloride (0.68 mol, 52.7 mL) was added toa stirring solution of 2,5-dibromo-3-picoline (0.45 mol, 113 g) inacetonitrile (600 mL) followed by sodium iodide (1.66 mol, 250 g) andthe reaction mixture was gently refluxed for 18 h. The cooled reactionmixture was filtered and the solid was washed with acetonitrile untilcolorless. It was suspended in methylene chloride and treated with aq.Na₂CO₃ until the pH was 10-11. The organic layer was separated, driedover anhydrous sodium sulfate and concentrated to give a brown oil. Itwas subjected to iodination a second time as above (reflux time 6 h). Adark brown oil was obtained using the same work-up as above. A solutionof this oil in hexane was treated with charcoal, filtered andconcentrated to give a light brown oil. It slowly solidified on standingto give 5-bromo-2-iodo-3-methylpyridine as a light brown solid (95.0 g,0.32 mol). Yield: 70%.

2-Iodo-5-bromo-3-methylpyridine (250 mg) was dissolved in THF (4.0 mL).The solution was cooled to 0° C. ^(i)PrMgCl (2 M in THF, 0.5 mL) wasadded at a rate to keep the internal temperature below 5° C. After thereaction mixture was stirred at 0° C. for 1 h, DMF (0.13 mL) was addedat 0° C. After stirring at this temperature for 30 min, the cooling bathwas removed and the reaction was allowed to warm to room temperatureover 1 h. The reaction mixture was hydrolyzed by a saturated aqueousNH₄Cl solution. Then the aqueous layer was extracted with CH₂Cl₂. TheCH₂Cl₂ layer was dried over MgSO₄ and concentrated to give the desiredaldehyde as a brownish-yellow solid (80% yield).

What is claimed is:
 1. A compound of the formula:

X_(a), is Br attached via the 5 ring position; X_(b) is chosen from Br,Cl and I; and W is CR₃ or N, wherein R₃ is chosen from hydrogen,C₁₋₅alkyl, C₁₋₅alkoxy and arylC₀₋₅alkyl.
 2. The compound according toclaim 1 wherein W is CH, C—CH₃ or N.
 3. The compound according to claim2 wherein the compound is chosen from:


4. A process of making a Grignard compound of the formula(F):

said process comprising: reacting a compound of the formula(C)

 with a magnesium reagent of the formula R—MgX_(b); said reaction takingplace in a suitable aprotic solvent at −78° C. to RT, for a reactiontime of ½ hour to 2 hours, producing the Grignard compound of theformula(F); and wherein X_(a) is Br attached via the 5 ring position;X_(b) is chosen from Br, Cl and I; X_(c) is I; W is CR₃ or N, wherein R₃is chosen from hydrogen, C₁₋₅alkyl, C₁₋₅alkoxy and arylC₀₋₅alkyl; and Ris chosen from aryl, C₁₋₆alkyl and C₅₋₇cycloalkyl.
 5. The processaccording to claim 4 wherein W is CH, CCH₃, or N.
 6. The processaccording to claim 5, wherein W is CH; the temperature is 0° C. to RT;and be reaction time is 1 hour.